This invention relates to a process for preparing a compound represented by the general formula (I): ##STR2## wherein R.sub.1 is a hydrogen atom or hydroxyl group, n stands for 0, 1 or 2, and A denotes a nitrogen-containing heterocyclic group or a direct bond coupling directly the sulfur atom and the --(CH.sub.2).sub.n COOH group together or a pharmaceutically acceptable salt thereof. More specifically, it relates to a process for preparing the compound of the general formula (I) or its pharmaceutically acceptable salt by reacting its corresponding phenylglycine derivative with 7-aminocephem derivative.
The compounds obtained in accordance with the process of this invention are useful as synthesis intermediates for antibacterial agents. The amino groups of the compounds of the general formula (I) may be acylated in a conventional manner, for example, those disclosed in Japanese Patent Application Laid-open No. 5487/1981, to prepare antibacterial agents.
Japanese Patent Application Laid-open No. 54580/1976 discloses a prior art preparation process of a compound represented by the general formula (I) by reacting its corresponding phenylglycine derivative with 7-aminocephem derivative. According to the above prior art process, N-t-butoxycarbonyl-p-hydroxyphenylglycine is reacted with 7-amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and the protecting group is then removed from the resultant reaction product to give 7-(.alpha.-amino-4-hydroxyphenylacetamido)-3-(1-carboxymethyltetrazol-5-yl thiomethyl)-3-cephem-4-carboxylic acid. In other words, the p-hydroxyphenylglycine is caused to undergo a reaction after its amino group has been protected with a t-butoxycarbonyl group. According to the above known literature, the above prior art process provided an extremely low yield, i.e., a yield of as low as about 5%.
It has also been known from U.S. Patent Specification No. 4,148,817 and Japanese Patent Application Laid-open No. 87189/1977 to obtain certain cephalosporin-type compounds by first reacting phenylglycine derivatives, whose amino groups have been protected in the enamine forms, with 7-aminocephem derivatives, removing the protecting groups using hydrochloric acid or nitric acid and then obtaining the cephalosporin-type compounds through their isoelectric point precipitation, although the cephalosporin-type compounds are different from the compounds represented by the general formula (I). The above preparation method was also tried in the initial stage of the present inventors' research on the syntheses of the compounds produced by the process of this invention. It was however found that, in the course of the isoelectric point precipitation after the removal of the enamine-form protection, intended products adhered as sticky substances on the reaction vessels and their post-treatment was indispensable to obtain them in crystalline form, thereby leading to lowered yields.